The overall goal of this proposal is to support the principal investigator, Dr. Daniel Westreich, in becoming a leading health scientist in the study of pregnancy among HIV+ women in sub-Saharan Africa, with a particular focus on the effect of pregnancy on response to highly active antiretroviral therapy (HAART) in South Africa. Prevalence of HIV among pregnant women in South Africa is substantially higher than that among other adults. While responses to antiretroviral therapy during and after pregnancy with respect to issues of prevention of mother to child transmission of HIV, little is known about the effect of pregnancy itself on responses to therapy. Understanding the effect of pregnancy on maternal responses to HAART is essential to providing good clinical care to HIV+ women in Africa and elsewhere. To address these questions, this work proposes to examine the effect of pregnancy (both pregnancy present at time of initiation of therapy, and pregnancy which occurs after the initiation of therapy) on virologic responses to HAART, adherence to HAART, retention in care, immunologic responses to HAART, and clinical (AIDS/death) responses to HAART. Because it is impossible (and highly unethical) to randomize the exposure of pregnancy, this study will rely on high quality clinical data collected in the Themba Lethu Clinic in Johannesburg, South Africa, an urban antiretroviral therapy clinic associated with the Clinical HIV Research Unit at the University of the Witwatersrand. The Principal Investigator of the proposed work, Dr. Daniel Westreich, has a strong track record in producing high quality research in collaboration with investigators and clinicians at the Clinic. The analysis of these data will require the use of structural models, an advanced body of epidemiologic methods. Thus, during the mentored phase of this award, Dr. Westreich will work with Mentor Dr. Stephen R. Cole, an internationally recognized authority on structural models, to acquire these skills and to evaluate the effect of pregnancy on maternal virologic responses to HAART. This training will take place in the Department of Epidemiology at The University of North Carolina at Chapel Hill, an internationally renowned center of excellence in epidemiologic and public health research. Building on this training and experience, during the independent phase of the award Dr. Westreich will lead investigations to evaluate the impact of pregnancy on retention in care and adherence to HAART, and on immunologic and clinical responses to HAART. This work will answer a suite of key substantive questions around the impact of pregnancy on response to HAART in South Africa. In doing so, this work will dramatically increase the base of scientific and public health evidence on this important subject, most likely in a way which is generalizable to much of sub-Saharan Africa. In addition, this work and training will help Dr. Westreich develop as a health scientist, giving him expertise in the application of structural models and other epidemiologic methods for quantitative causal inference in complex longitudinal data.